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Molecular characterization of congenital hyperinsulinism/hyperammonemia caused by glutamate dehydrogenase gene defects

Research Project

Project/Area Number 15390687
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionOsaka City University

Principal Investigator

OKANO Yoshiyuki  Osaka City University, Department of Pediatrics, Lecturer, 大学院・医学研究科, 講師 (60231213)

Co-Investigator(Kenkyū-buntansha) INADA Hiroshi  Osaka City University, Department of Pediatrics, Lecturer, 大学院・医学研究科, 講師 (00244640)
KAWAMURA Tomoyuki  Osaka City University, Department of Pediatrics, Assistant Professor, 大学院・医学研究科, 助手 (60271186)
KUNO Miyuki  Osaka City University, Department of physiology, Research Assistant, 大学院・医学研究科, 助教授 (00145773)
MIYAZAKI Jyun-ichi  Osaka University, Graduate School of Medicine, Division of Stem Cell Regulation Research, Professor, 大学院・医学系研究科, 教授 (10200156)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2004: ¥2,900,000 (Direct Cost: ¥2,900,000)
Keywordsglutamate dehydrogenase / insulin / hyperammonemia / hypoglycemia / mutation / K_<ATP> channel / nonselective cation channel / KATPチャンネル / 先天性代謝異常症 / 高インスリン血症 / アデノウィルス
Research Abstract

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by "gain of function" of glutamate dehydrogenase (GDH). Several missense mutations have been found ; however, cell behaviors triggered by the excessive GDH activity have not been fully demonstrated. This study was aimed to clarify electrophysiological mechanisms underlying the dysregulated insulin secretion in pancreatic beta cells with GDH mutations. GDH kinetics and insulin secretion were measured in MIN6 cells overexpressing the G446D and L413V. Membrane potentials and channel activity were recorded under the perforated-patch configuration that preserved intracellular environments. In mutant MIN6 cells, sensitivity of GDH to guanosine triphosphate (GTP) was reduced and insulin secretion at low glucose concentrations was enhanced. The basal GDH activity was elevated in L413V bearing a mutation in the antenna-like structure. The L413V cells were depolarized without glucose, often accompanying by repetitive Ca^<2+> firings. The depolarization was maintained in the presence of adenosine triphosphate (ATP) and disappeared by depleting ATP, suggesting that the depolarization depended on intracellular ATP. In L413V cells, the ATP-sensitive potassium channel (KATP channel) was suppressed and the nonselective cation channel (NSCC) was potentiated, while sensitivity of the channels to their specific blockers or agonists was not impaired. These data suggest that the L413V cells increase the intracellular ATP/adenosine diphosphate (ADP) ratio, which in turn causes sustained depolarization not only by closure of the KATP channel, but also by opening of the NSCC. The resultant activation of the voltagegated Ca^<2+> channel appears to induce hyperinsulinism. The present study provides evidence that multiple channels cooperate in unregulated insulin secretion in pancreatic beta cells of the HI/HA syndrome.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (10 results)

All 2006 2005 2004

All Journal Article (10 results)

  • [Journal Article] Unregulated insulin secretion by pancreatic β cells in hyperinsulinism/hyperammonemia syndrome : role of glutamate dehydrogenase, ATP-sensitive potassium channel, and nonselective cation channel.2006

    • Author(s)
      Kawajiri M
    • Journal Title

      Pediatr Res 59・3

      Pages: 359-364

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Unregulated insulin secretion by pancreatic beta cells in hyperinsulinism/hyperammonemia syndrome : role of glutamate dehydrogenase, ATP-sensitive potassium channel, and nonselective cation channel.2006

    • Author(s)
      Kawajiri M, Okano Y, Kuno M, Tokuhara D, Hase Y, Inada H, Tashiro F, Miyazaki J, Yamano T.
    • Journal Title

      Pediatr Res 59・3

      Pages: 359-364

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Diffusion-weighted MR imaging in patients with phenylketonuria : relationship between serum phenylalanine levels and ADC values in cerebral white matter.2005

    • Author(s)
      Kono K
    • Journal Title

      Radiology 236・2

      Pages: 630-636

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Diffusion-weighted MR imaging in patients with phenylketonuria : relationship between serum phenylalanine levels and ADC values in cerebral white matter.2005

    • Author(s)
      Kono K, Okano Y, Nakayama K, Hase Y, Minamikawa S, Ozawa N, Yokote H, Inoue Y.
    • Journal Title

      Radiology. 236・2

      Pages: 630-636

    • Related Report
      2005 Annual Research Report
  • [Journal Article] In vivo studies of phenylalanine hydroxylase by phenylalanine breath test : diagnosis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency2004

    • Author(s)
      Okano Y
    • Journal Title

      Pediatr Res 56・6

      Pages: 714-719

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of citrin deficiency in the perinatal period : feasibility of newborn mass screening for citrin deficiency.2004

    • Author(s)
      Tamamori A
    • Journal Title

      Pediatr Res 56・4

      Pages: 608-614

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] In vivo studies of phenylalanine hydroxylase by phenylalanine breath test : diagnosis of Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.2004

    • Author(s)
      Okano Y
    • Journal Title

      Pediatr Res 56・6

      Pages: 714-719

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] In vivo studies of phenylalanine hydroxylase by phenylalanine breath test : diagnosis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.2004

    • Author(s)
      Okano Y, Hase Y, Kawajiri M, Nishi Y, Inui K, Sakai N, Tanaka Y, Takatori K, Kajiwara M, Yamano T
    • Journal Title

      Pediatr Res. 56

      Pages: 714-719

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effects of citrin deficiency in the perinatal period : feasibility of newborn mass screening for citrin deficiency.2004

    • Author(s)
      Tamamori A, Fujimoto A, Okano Y, Kobayashi K, Saheki T, Tagami Y, Takei H, Shigematsu Y, Hata I, et al.
    • Journal Title

      Pediatr Res. 56

      Pages: 608-614

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Long-term treatment and diagnosis of tetrahydrobiopterin-respomsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene2004

    • Author(s)
      Shintaku H, Kure S, Ohura T, Okano Y, Ohwada M, Sugiyama N, Sakura N, Yoshida I, Yoshino M, et al.
    • Journal Title

      Pediatr Res. 55

      Pages: 425-430

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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